Substituted nitroimidazoles and method of preparing the same

ABSTRACT

THIS INVENTION RELATES TO THE NOVEL 1-BENZOYLOXIMINO1- (1-SUBSTITUTED-5-NITRO-2-IMIDAZOLY)-2-PHENYL-GLOYXALS, A METHOD FOR THE PREPARATION THEREOF AND THE USE OF SUCH COMPOUNDS AS INTERMEDIATES IN THE PREPARATION OF THE ANTIBACTERIAL AND ANTIPROTOZOAL COMPOUNDS 2-AMINO-5-N5NITRO-1-SUBSTITUTED-2-IMIFSXOLYLZ)-1,3,4-THIADIAZOLES.

United States Patent U.S. Cl. 260--309 7 Claims ABSTRACT OF THEDHSCLGSURE This invention relates to the novel l-benzoyloximino- 1(l-substituted-S-nitro-2-imidazoly)-2-phenyl-glyoxals, a method for thepreparation thereof and the use of suchv compounds as intermediates inthe preparation of the antibacterial and antiprotozoal compoundsZ-amino-S-(S- nitro-l-substituted-Z-imidazolyl)-1,3,4-thiadiazoles.

SUMMARY OF THE INVENTION The present invention is particularly directedto new l benzoyloximino 1(1-substituted-5-nitro-2-imidazolyl)-2-phenylglyoxal compounds havingthe formula:

wherein R is lower alkly, loweralkanoyloxyloweralkyl oraroyloxyloweralkyl and R is phenyl, monohalophenyl, dihalophenyl,loweralkylphenyl, diloweralkylphenyl, 4- nitrophenyl, methoxyphenyl ornaphthyl. The term loweralkyl and loweralkanoyl, as used throughout thisspecification and appended claims, is intended to mean straight andbranched chain alkyl groups or alkanoyl groups having from 1 to 4 carbonatoms. The term aroyl is intended to include benzoyl, monohalobenzoyl,dihalobenzoyl, loweralkylbenzoyl, diloweralkylbenzoyl, 4- nitrobenzoyl,methoxybenzoyl and naphthoyl. The term halo is intended to includefluorine, chlorine, bromine and iodine and dihalophenyl describes aphenyl substituted with two halogens which are either the same orditferent. Similarly, the term diloweralkylphenyl describes a phenylsubstituted with two identical or different alkyl groups, eitherstraight or branched chain and having from 1 to 4 carbon atoms. Thisinvention is also concerned with a novel method for the preparation ofthe above compounds and the use of such compounds as antibacterialagents or as intermediates in the preparation of the 2 amino5-(S-nitro-1-substituted-Z-imidazolyl)- 1,3,4-thiadiazoles which arehighly effective antibacterial and antiprotozoal agents.

In regard to the new compounds of the present invention (i.e., 1benzoyloximino 1 (l-substituted-S-nitro- 2-imidazolyl)-2-phenylglyoxals)having the formula:

wherein R and R are defined above, it is pointed out that where R ismonohalophenyl or loweralkylphenyl the halogen or alkyl may be in theortho, meta or para positions and the preferred substituents are chloroand bromo for the halo group and methyl, ethyl or isopropyl for theloweralkyl group. Where R is dihalophenyl or diloweralkylphenyl andsubstituents may be located in any two of the 2,3,4,5 or 6-position onthe phenyl ring and the halogens or loweralkyl substituents may be thesame or 3,634,447 Patented Jan. 11, 1972 different. The preferreddihalophenyl groups are the dichloro, dibromo and the chlorobromophenylgroups such as, 2,3-dichlorophenyl; 3,4-dichlorophenyl;3,5-dichlorophenyl, 2,6-dibromophenyl; 3,5-dibromophenyl; 2-chloro-3-bromophenyl; 3-chloro-5-phenyl and 3-bromo-4-chlorophenyl. Thepreferred diloweralkylphenyl group are the 3,4 dimethylphenyl; 3,5dimethylphenyl; 2,6-diethyphenyl; 2,3 diethylphenyl;3-isopropyl-4-methy1phenyl; 3 isopropyl 5 methylphenyl; the3,5-diisopropylphenyl and the 3,4-diisopropylphenyl.

These compounds may be prepared by reacting a l-substituted 5nitro-a-phenyI-Z-imidazoleethenolbenzoate of the formula 0 N ll I I(|)CRi O N -o1-I=o-R,

wherein R and R are as defined above, with at least about 1 moleequivalent of a nitrosating agent selected from the group consisting ofnitrosyl chloride, nitrosyl bisulfate, nitrogen dioxide or tetroxide,nitrogen trioxide and nitrogen pentoxide. The reaction may be conductedat atmospheric or superatmospheric pressure over a temperature range offrom about 0 C. to C. and is preferably conducted at a temperaturebetween about 20 C. and 80 C. The reaction generally requires from about10 minutes to 4 hours for completion but this time may be extended toabout 24 hours if desired. In most instance it is generally expedient toconduct these reactions at atmospheric pressure; however, when desirableto do so, such reactions may be conducted under several atmospheres ofpressure generally not exceeding about 10 atmospheres. It is usuallyalso found to be most practicable to conduct these reactions employingan excess of nitrosating agent. A slight excess is generally sufficientto give optimum product yields but on occasion it may be desirable toemploy a large excess of nitrosating agent, for example, 2 or 3 moleequivalents of nitrosating agent per mole of imidazoleethanol benzoate.Even larger excesses of nitrosating agent (i.e., as much as 10 moleequivalents per mole of imidazoleethanol benzoate) may be used in thesereactions but usually there is little if any further improvement inproduct yield obtained over that obtained with a 2 or 3 mole equivalentexcess.

It has also been found that this reaction can advantageously beconducted in the presence of an alkali metal salt of an organic acidsuch as sodium or potassium acetate, propionate, butyrate or the like.Usually, such salt when present are used in approximately equimolaramounts with the nitrosating agent. However, greater or lesser amountsmay be employed, for example, from about 0.5 to 2 mole equivalents ofacid salt may be used per mole of nitrosating agent. It has further beendiscovered that this process may, advantageously, be conducted in thepresence of an organic solvent inert with respect to the reactants andthe chemical reaction. Among the solvents suitable for this purpose arethe monocyclic hydrocarbons such as toluene and benzene, the chlorinatedhydrocarbons such as methylene chloride or ethylene chloride, alsoacetonitrile and nitromethane.

The starting materials (i.e., thel-substituted-S-nitroa-phenyl-Zdmidazoleethenol benzoates) for thesereactions are obtained from 1-loweralkyl-, l-hydroxyloweralkyl-,1-loweralkanoyloxyloweralkyl-, orl-aroyloxyloweralkyl-Z-methyl-S-nitroimidazoles by reaction with from 2to 8 moles of an acid halide at a temperature of about 25 C. to C. for 3to 24 hours in an inert solvent in the presence of a tertiary amine suchas, for example, triethylamine or diisopropylethylamine. Acid halidesfound useful in the reaction may be, for example, benzoyl chloride,halobenzoyl chloride, dihalobenzoyl chlorides, lower alkylbenzoylchlorides, dilower alkyl benzoyl chlorides, p-nitrobenzoyl chloride,naphthoyl chloride, or benzoyl bromide. Solvents such astetrahydrofuran, diglyme, toluene, and the like can be used.

A suflicient quantity of a tertiary amine such as diisopropylethylamineis used both to catalyze the reaction and to react with the hydrogenhalide liberated. For example, refluxing 0.2 mole of1,Z-dimethyl-S-nitroimidazole and 0.6 mole of benzoyl chloride in 125ml. of diisopropylethylamine and 75 ml. of dioxane for 18 hours givesl-methyl-S-nitro-ot-phenyl-2-imidazoleethenol benzoate in high yield.

The reaction may be illustrated as follows:

wherein R and R are as previously defined.

As previously indicated, the compounds of the present invention areuseful as antibacterial agents. In particular, they are effective inchickens for the control of Salmonella gallinarum the causative agent offowl typhoid when employed at the concentration of 0.1 to 0.75%administered in the feed and are also etfective for controlling certainprotozoal infections such as Trichomonas vaginalis. These compounds arealso useful as intermediates in the preparation of the nitroimidazolesdescribed in Berkelhammer et al., US. Pat. 3,452,035 issued June 24,1969. These nitroimidazoles are shown to be highly effectiveantibacterial and antiprotozoal agents useful in the treatment ofbacterial and protozoal infections in poultry and other domestic andfarm animals.

The procedures which may be employed to obtain the nitroimidazoles ofthe above-mentioned patent are graphically illustrated in the flowdiagram below.

FLOW DIAGRAM OzNl J-ON N N l 1 OBN N C (from Formula I whereR=loweralkanoyloxyloweralkyl or aroyloxyloweralkyl) imidazole of FormulaII by reaction thereof with 1 mole equivalent of a strong base,preferably an alkali metal hydroxide, cyanide or alkoxide such as sodiumhydroxide, potassium hydroxide, potassium cyanide, sodium cyanide,potassium t-butoxide, sodium methoxide or sodium ethoxide, at atemperature between about 0 C. and C. and preferably between about 2030C. In practice it is usually also desirable to conduct this reaction inthe presence of an organic solvent such as the loweralkyl alcoholshaving from 1 to 6 carbon atoms. While the above reaction is optimallyrun using 1 molar equivalent of base, it has been found that a lowerratio of base to phenylglyoxal yields a correspondingly lesser amount ofthe Formula II nitroimidazole.

When the Formula I compound is treated as described immediately above inan alcoholic solvent, but an excess of base is used over the 1 moleequivalent used to form the Formula II nitroimidazole, the reactionproceeds directly to the imidazolecarboximidate of Formula III. Whileonly a catalytic amount of base in excess of the 1 mole equivalent isrequired for this reaction, 2 or even 3 mole equivalents of base may beemployed. However, larger excesses of base appear to have no advantagein this process. In this reaction R is as described above and Rrepresents the alkyl group derived from the solvent employed.

Also, where R is acyloxy loweralkyl, the phenylglyoxal of the Formula Iundergoes transesterification during the course of the reaction and iscyclized to the cyclic imidate of Formula III. As with the abovereaction, the alkali metal hydroxides, cyanides, and alkoxides arepreferred bases and the 1 to 6 carbon alcohols are preferred solvents.

The imidazolecarboximidates of Formula III are then readily converted tothe imidazolecarboximidoyl thiosemicarbazides of Formula IV by reactionof the imidazolecarboximidate with approximately an equimolar amount ofa thiosemicarbazide of the formula S R3 HzNNHt iN wherein R and R arehydrogen or loweralkyl and a catalytic or greater amount of an organiccarboxylic acid such as acetic, benzoic, propionic, butyric orequivalent acid. The-reaction may be run over a temperature range ofabout 0 C. to 100 C. and in the presence of an organic solvent such asdefined above for the previous steps. Alternatively, a catalytic amountof a mineral or strong organic acid such as a sulfonic acid or trifluoroacetic acid may be used, providing the temperature is kept between 0 C.and about 30 C.

If this same reaction is run substituting a mineral acid such ashydrochloric, hydrobromic, sulfuric acid or the like or an organic acidsuch as a sulfonic acid or trifiuoroacetic acid for the carboxylic acid,and the reaction mixture is heated to between about 45 C. and C., thethiadiazoles of Formula V are obtained directly from the reactionmixture. Formula V compounds are useful as antibacterial orantiprotozoal agents in the treatment of domestic and farm animals. Theimidazolecarboximidoyl thiosemicarbazides of Formula IV are also readilyconverted to the2-amino-5-(S-nitro-1-substituted-Z-imidazolyl)-1,3,4-thiadiazoles ofFormula V by treatment thereof with a catalytic amount of a mineral acidor a sulfonic acid or a strong organic acid as mentioned above, andheating of the reaction mixture to between 45 C. and 150 C.Alternatively, the ring closure to the thiadiazole may be carried out ina strong liquid acid such as trifiuoroacetic acid or hydrofluoric acidin the absence of an appreciable amount of added solvent at somewhatlower temperatures, for example 0 to 45 C.

While the Formulae III and 1V compounds may be isolated from theirseparate reaction mixtures, it has been found that such products neednot be isolated if one wishes simply to conduct the process in astepwise manner adding the required reactants to the reaction mixture atthe appropriate time following completion of the previous reaction.

By referring to the flow diagram it can be seen that the phenylglyoxalof Formula I can be converted to the thiadiazole of Formula V in atelescoped process. This involves the steps of 1) treating thephenylglyoxal Formula I with at least 1 mole equivalent plus a catalyticamount and preferably 2 mole equivalents of a strong base selected fromthe group consisting of alkali metal hydroxide, alkali metal cyanidesand alkali metal alkox ides, in the presence of a C C alcohol, (2)treating the thus formed mixture with a thiosemicarbazide, with acatalytic amount of an organic or mineral acid present, and (3) heatingthe thus formed reaction mixture with a catalytic amount of a strongmineral acid or a strong organic acid preferably selected from the groupconsisting of hydrohalic acids, sulfur containing mineral acids,sulfonic acid or trifiuoroacetic acid. In step (2) above thethiosemicarbazide has the formula wherein R and R are hydrogen orloweralkyl C -C SPECIFIC DISCLOSURE The following examples illustrate indetail the preparation of representative compounds of this invention.

EXAMPLE 1 Preparation of 1-benzoyloximin0-1-[ l-methyl-S-nitro-Z-imidazolyl -2-phenylglyoxal (A) A mixture of 28.7 g. (0.020 mole) of1,2-dimethyl- S-nitroimidazole, 125 ml. of diisopropylethylamine, 75 ml.of dioxane and 70 ml. (84 g., 0.60 mole) of benzoyl chloride, isrefluxed for 18 hours. After standing and cooling to room temperature,300 ml. of ether is added to the crystalline mass. The solid is brokenup and filtered and washed with ether. The solid is Washed with two100-ml. portions of water and with ether to give 59 g. of l-methyl-S-nitrO-a-phenyl 2 imidazoleethenol benzoate, melting point 194198 C.,raised to 205-207 C. by recrystallization.

(B) Trimethylamine, 33.8 g. (0.573 mole), is dissolved in 120 ml.toluene. This solution is mixed with 20 g. (0.1415 mole)1,2-dimethyl-5-nitroimidazole and 41 n1]. (0.3540 mole) of benzoylchloride. The mixture is mechanically stirred overnight at about roomtemperature. The resulting bright yellow precipitate is filtered, mixedwith 50 ml. water, washed three times with a total of 150 ml. water anddried in a hot air oven to constant weight. There is obtained 47.7 g.(97%) of same product as A above, melting point 200 to 202 C., and205207 C. after recrystallization.

Other compounds which are prepared according to the above-describedprocedure are, for example, l-methyl-S- nitro-a-(4-chlorophenyl) 2imidazoleethenol 4-chlorobenzoate; l-methyl 5 nitro a (2,4dichlorophenyl)- 2-imidazoleethenol 2,4-dichlorobenzoate, andl-methyl-S- nitro a (2,4,6 tribromophenyl) 2 imidazoleethenol2,4,6-tribromobenzoate.

To a mechanically stirred mixture ofl-methyl-S-nitroa-phenyl-Z-imidazoleethenol benzoate (7.0 g., 0.02 mole)and 30 ml. of acetonitrile cooled to 6 C. is added liquid dinitrogentetroxide (2.76 g., 1.9 ml., 0.03 mole) and the mixture is stirred atroom temperature for 20 hours. The solid is filtered, washed withacetonitrile and dried, afiording 2.59 g. of the benzoyloxime, meltingpoint 147150 C. The filtrate is concentrated, diluted with Water andadjusted to pH 8 with 10% sodium bicarbonate solution. The solid isfiltered, washed and dried yielding an additional 4.38 g. of product,melting point 146-l50 C.

The above procedure, using dichloroethane or toluene as solvent, alsogives1-benzoyloximino-1-(l-methyl-S-nitro-2-imidazolyl)-2-phenylglyoxal.

EXAMPLE 2 Preparation of l-benzoyloximino-1- lmethyl-S-nitro-2-imidazolyl -2-phenylglyoxal To a magnetically stirred mixture ofl-methyl-S-nitrou-phenyl-2-imidazoleethanol benzoate (17.5 g., 0.05mole) and 200 ml. of nitromethane (dried over molecular sieves), cooledto 5 C., is added liquid dinitrogen tetroxide (6.9 g., 4.8 ml., 0.075mole). The mixture is stirred at room temperature for 4 hours and theexcess dinitrogen tetroxide is removed under a stream of air. The yellowsolution is evaporated to dryness and the residue is slurried with cold10% sodium bicarbonate solution. The tan solid is filtered and washedwith water, aifording 19.2 g. of the title compound, melting point143-147 C. A sample is recrystallized from benzene-heptane affordingpure product, melting point 149151 C.

When the two phenyl groups in the starting material are replaced by4-chlorophenyl; 2,4-dichlorophenyl; 4-nitrophenyl; 4-tolyl; 2,4-xylyl;2,4-dimethoxyphenyl; or anaphthyl, there is obtained by use of the aboveprocedure 1- (4-chlorobenzoyl oximino-1-( l-methyl-S-nitro-Z- imidazolyl-2- 4-chlorophenyl glyoxal 1- (2,4-dichlorobenzoyl oximino-1-(l-methyl-S-nitro- Z-imidazoyl) -2- 2,4-dichlorophenyl glyoxal1-(4-nitrobenzoyl)oximino-1-( l-methyl-S-nitro-Z- imidazolyl -2-4-nitrophenyl) glyoxal;

1-(4-toluyl)oximino-1-( 1-methyl-5-nitro-2-imidazolyl)- 2- (4-tolylglyoxal;

1-(2,4-xyloyl)oximino-1-( l-methyl-S-nitro-Z- imidazolyl -2- (2,4-xylylglyoxal;

1-(2,4-dimethoxybenzoyl)oximino-1-( 1-methyl-5-nitro- Z-imidazolyl -2-2,4-dimethoxyphenyl glyoxal; and

1- a-naphthoyl) oximino-l- (methyl-S-nitro-Z-imidazolyl -2- a-naphthylglyoxal respectively.

EXAMPLE 3 Preparation of 1-benzoyloximino-1-( l-methyl-S-nitro-Z-imidazolyl) -2-phenylglyoxal To a mechanically stirred mixture ofl-methyl-S-nitroa-phenyl-2-imidazoleethanol benzoate (1.75 g., 0.005mole) and 50 m1. of nitromethane cooled to 5 C. is added liquid nitrogentrioxide (1.3 g., 0.9 ml., 0.017 mole). The mixture is stirred at roomtemperature for 4 /2 hours and the excess nitrogen trioxide isevaporated under a stream of air. The solution is evaporated to drynessand the residue is slurried with cold water and made alkaline with cold10% sodium bicarbonate solution. The solid is filtered, washed, anddried, affording 1.72 g. of the benzoyloxime. Recrystallization frombenzene-heptane gives product with melting point 149151 C.

EXAMPLE 4 Preparation of 1-benzoy1oximino-1-( l-methyl-S-nitro-Z-imidazolyl -2-phenylglyoxal To a mechanically stirred slurry of sodiumacetate (0.82 g., 0.01 mole) in 50 ml. of nitromethane cooled to 5 C. isadded liquid dinitrogen tetroxide (0.92 g., 0.64 ml., 0.01 mole) and themixture is stirred at room temperature for 1% hours. To the mixture isadded l-methyl- 5-nitro-u-phenyl-2-imidazoleethanol benzoate (1.75 g.,0.005 mole) and the mixture is stirred at room temperature for 2 hours.The white solid is filtered and washed with nitromethane, affording0.824 g. of sodium nitrate. The filtrate is evaporated to dryness andthe residue is slurried with Water and 10% sodium bicarbonate solution.The solid is filtered, Washed and dried afiording 1.867 g. of thebenzoyloxime, described above, melting point 141 146 C.

7 EXAMPLE Preparation of 1-benzoyloximino-1-(l-methyl-S-nitro-2-imidazolyl -2-phenylglyoxal Nitrosyl chloride is bubbled into amagnetically stirred solution of1-methyl-5-nitro-tat-phenyl-Z-imidazoleethanol benzoate (1.75 g., 0.005mole) in 50 ml. of dry benzene for 1% hours at room temperature and for1% hours at 70-80 C. The reaction mixture is cooled and the excessnitrosyl chloride is evaporated under a stream of air. The reactionmixture is evaporated to dryness and the residue is slurried withheptanebenzene (5:1) and cooled in an ice bath. The solid is filteredafiording 1.12 g. of white solid. Recrystallization from benzene heptaneaffords 0.85 g. of the benzoyloxime, melting point 149-15l C.

EXAMPLE 6 Preparation of 2-cyano-1-methyl-5-nitroimidazole A mixture of1-methyl-5nitro-a-phenyl-2-imidazoleethanol benzoate (1.75 g., 0.005mole) and 50 ml. of dry benzene is stirred and heated to reflux andnitrosyl chloride is bubbled into the refluxing solution for 1 hour. Thereaction mixture is cooled and evaporated to dryness, affording an oil.The residue is slurried with ether-hexane (1:1) and several ml. ofethanol is added along with sodium bicarbonate solution. The mixture isstirred for 2 hours, and the solid is filtered, washed and dried,affording 0.20 g. of l-benzoyloximino-1(l-methyl-5-nitro-2-imidazolyl)-2-phenylglyoxal. The filtrate is concentrated and extractedwith carbon tetrachloride. The aqueous layer is extracted withchloroform and the extracts are evaporated to dryness, affording theabove compound identified by comparison of the infrared spectrum withthat of an authentic sample.

EXAMPLE 7 Preparation of 1-benzoyloximino-1-(l-ethyl-S-nitro-Z-imidazolyl) -2-phenylglyoxal To a stirred solution of1-ethyl-5-nitro-a-phenyl-Z- imidazoleethenol benzoate (0.90 g., 0.002mole) in 25 ml. of dry nitromethane is added liquid dinitrogen tetroxide(0.46 g., 0.31 ml. 0.005 mole) and the solution is stirred at roomtemperature for 3 /2 hours. The excess dinitrogen tetroxide isevaporated under a stream of air and the reaction mixture is evaporatedto dryness. The oily residue is treated with 50 ml. of water and madealkaline with a saturated sodium bicarbonate solution. The mixture iscooled and the solid is filtered, washed and dried affording 0.89 g. ofcrude product, melting point 126144 C. The solid is recrystallized frombenzene-heptane afiording 0.64 g. of pure title compound, melting point149- 151 C.

EXAMPLE 8 Preparation ofl-benzoyloximino-l-[1-(2-benzoyloxyethyl)-5-nitro-2-imidazolyl]-2-phenylglyoxalTo a stirred mixture of 1-(2-benzoyloxyethyl)-5-nitro-a-phenyl-Z-imidazoleethenol benzoate (2.42 g., 0.005 mole) and 50ml. of dry nitromethane cooled to 10 C. is added liquid dinitrogentetroxide, and the mixture is stirred at room temperature for 4 /2hours. The excess dinitrogen tetroxide is evaporated under a stream ofair and the reaction mixture is evaporated to dryness. The oily residueis slurried with 50 ml. of water and made alkaline with 10% sodiumbicarbonate solution. The solid is filtered, washed and dried affording2.53 g. of crude product. The solid is recrystallized frombenzene-heptane to give 1.98 g. of pure title compound, melting point127- 129 C.

In a similar manner 1 benzoyloximino 1 [1-(2- acetoxy-ethyl) 5 nitro 2imidazolyl] 2 phenylglyoxal is prepared from 1 (2 acetoxyethyl) 5 nitro-0L-Phl1y1 2 imidazoleethenol benzoate.

8 EXAMPLE 9 Preparation of 1-benzoyloximino-1-(l-methyl-S-nitro-2-imidazolyl)-2-phenylglyoxal To a mixture of 7.3 g. of nitrosylsulfuricacid in 30 m1. of dry acetonitrile chilled in an ice bath is added 7.0g. (0.020 mole) of 1 methyl 5 nitro a phenyl-Z- imidazoleethanolbenzoate. The mixture is chilled for 15 minutes and stirred at roomtemperature for 17 hours. The mixture is poured onto ice and made basicwith saturated sodium bicarbonate solution. Filtration gives 6.6 g. ofyellow crystals. Purification gives the product 1 (1 methyl 5 nitro 2imidazolyl) 2 phenylglyoxal l-(o-benzoyloxime) as pale yellow crystals,melting point 148-151 C.

EXAMPLE 10 Preparation of 2-cyano-1-methyl-5-nitroimidazole To amagnetically stirred mixture of potassium cyanide (0.326 g., 0.005 mole)and 50 ml. of absolute ethanol is added 1 benzoyloximino 1 (1 methyl 5nitro- 2 imidazolyl) 2 phenylglyoxal (1.90 g., 0.005 mole). Theresulting mixture is stirred at room temperature for minutes and thesolid is filtered. The filtrate is evaporated to dryness and the residueis slurried with 50 ml. of heptane and the resultant solid is filtered,washed with heptane, then slurried with water and extracted withchloroform. The chloroform extracts, upon evaporation, yield 0.64 g. ofoil, which solidifies on cooling. The product melts at 76-86 C. and hasan infrared spectrum identical to authenticl-methyl-5-nitroimidazole-Z-carbonitrile.

In a similar manner, 2-cyano-1-ethyl-5-nitroimidazole, 1 (2acetoxyethyl) 2 cyano 5 nitroimidazole and 1 (2 benzoyloxyethyl) 2 cyano5 nitroimidazole are prepared from 1 benzoyloximino 1 (1 ethyl-5- nitro2 imidazolyl) 2 phenylglyoxal, 1 benzoyloximino 1 [1 (2 acetoxyethyl) 5nitro 2 imidazolyl] 2 phenylglyoxal and 1 benzoyloximino 1 [1- (2benzoyloxyethyl) 5 nitro 2 imidazolyl]-2- phenylglyoxal, respectively.

According to the above procedure, 2-cyano-1-methyl-5- nitroimidazole isprepared from l-benzoyloximino-l-(lmethyl 5 nitro 2 imidazolyl) 2phenylglyoxal by replacing the potassium cyanide in ethanol with anequimolar amount of sodium methoxide in methanol.

EXAMPLE 1 1 Preparation of ethyl l-methyl-S-nitro-Z-imidazolecarboximidate To a magnetically stirred solution of potassiumtbutoxide (0.62 g., 0.0055 mole) in 50 ml. of absolute ethanol is added1-benzoyloximino-1-(l-methyl-S-nitro-Z- imidazolyl)-2-phenylglyoxal(1.90 g., 0.005 mole) and the mixture is stirred at room temperature for30 minutes. Additional potassium t-butoxide is aided to make the mixturealkaline to pH paper. The mixture is stirred for an additional 3 hoursand the solid is filtered and discarded. The filtrate is evaporated todryness and the residue is washed with ml. of hot heptane. The heptanesolution is concentrated and cooled in an ice bath. The resulting paleyellow needles are filtered, affording 0.69 g. of ethyl imidate, meltingpoint 72-79 C.

The ethyl imidate is also obtained from l-benzoyloximino 1 (1 methyl 5nitro-Z-imidazolyl)-2-phenylglyoxal with 2 mole of potassium cyanide inethanol for each mole of 1 benzoyloximino 1 (1 methyl-5- nitro 2imidazolyl) 2 phenylglyoxal.

According to the above procedure, ethyl 1-ethyl-5- nitroimidazole 2carboximidate is prepared from 1- benzoyloximino 1 (1 ethyl 5 nitro 2imidazolyl)- 2-phenylglyoxal.

In a similar manner 1 (2 hydroxyethyl) 5 nitro- 2 imidazolecarboximidicacid delta-lactone is prepared from both 1 benzoyloximino 1 [1acetoxyethyl)- 9 5 nitro 2 imidazolyl] 2 phenylglyoxal and 1-benzoyloximino 1 [1 (2 benzoyloxyethyl) 5 nitro- 2-imidazolyl]-2-phenylglyoxal.

In a similar manner, methyl 1-methyl-5-nitro-2-imidazolecarboximidate isprepared from 1 benzoyloximino-1- (1 methyl 5 nitro 2 imidazolyl) 2phenylglyoxal by replacing the potassium t-butoxide in ethanol by anequimolar amount of sodium methoxide in methanol.

EXAMPLE 12 Preparation of 1-(1-methyl-5-nitro-2-imidazolecarboximidoyl)-3-thiosemicarbazide To a mechanically stirred solution of sodiummethoxide (0.594 g., 0.011 mole) in 20 ml. of methanol is added 1benzoyloximino 1 (1 methyl 5 nitro 2 imidazolyl) 2 phenylglyoxal (3.78g., 0.01 mole). A temperature of 23 -25 C. is maintained during theaddition. Additional sodium methoxide is added to give pH 10 and themixture is stirred at room temperature for 2 /2 hours. To this solutionof methyl 1 methyl 5 nitro-2- imidazolecarboxirnidate, thiosemicarbazide(0.91 g., 0.01 mole) and 1 ml. of glacial acetic acid are added and theyellow mixture is stirred at room temperature for 3 hours. The reactionmixture is cooled and the red-orange solid is filtered and dried,affording 1.87 g. of the title compound, melting point l96-206 C.Recrystallization from ethanol-dimethyl formamide gives pure product,melting point 208210 C. with decomposition.

The title compound is also obtained when the above procedure is usedwith the execption that the following compounds are substituted for thel-benzoyloximino-ll-methyl-5nitro-2-imidazolyl) -2-phenylglyoxal;namely,

1-(4-chlorobenzoyl)oximino-1-( 1-methyl-5-nitro- 2-imidazolyl) -2-(4-chlorophenyl) glyoxal;

1-(2,4-dichlorobenzoyl)oximino-1-( l-methyl-S- nitro-Z-imidazolyl) -2-2,4-dichlorophenyl) glyoxal;

1- 4-m'trobenzoyl) oximinol-( 1-methyl-5-nitro-2- imidazolyl) -2-(4-nitrophenyl glyoxal;

1- (4-toloyl oximino-1-( 1-methyl-5-nitro-2-imidazolyl) 2-(4-toluyl)-glyoxal;

1- 2,4-xyloyl) oximino-1-( 1-methyl-5nitro-2-imidazolyl)- 2- 2,4-xylyl)glyoxal;

1- 2,4-dimethoxybenzoyl oximinol-( l-methyl- 5-nitro-2-imidazolyl -2-2,4-dimethxyphenyl) glyoxal; and

1- (a-naphthoyl) oximino-1-( 1-methyl-5-nitro-2- imidazolyl) -2-a-naphthyl) glyoxal.

By the above procedure, 1 (1 methyl nitro-2- imidazolecarboximidoyl) 4methyl 3 thiosemicarbazide and 1 (l methyl 5 nitro 2imidazolecarboximidoyl 4,4 dimethyl 3 thiosemicarbazide are obtained byreplacing thiosemicarbazide with 4- methyl 3 thiosemicarbazide and 4,4dimethyl-3-thiosemicarbazide; respectively.

EXAMPLE 13 Preparation of l-[1-(2-hydroxyethyl)-5-nitro-2-imidazolecarboximidoyl] -3-thiosemicarbazide To a stirred solution ofsodium methoxide (0.13 g., 0.0024 mole) in 25 ml. of methanol is addedl-benzoyloximino 1 [1 (2 benzoyloxyethyl) 5 nitro 2- imidazolyl] 2phenylglyoxal (1.024 g., 0.002 mole) and the solution is stirred at roomtemperature for 2 /2 hours. Thiosemicarbazide (0.182 g., 0.002 mole) and1 ml. of glacial acetic acid are added and the mixture is stirred atroom temperature for 18 hours. The reaction is cooled in an ice bath andthe solid is filtered, washed and dried to give 0.478 g. of the titlecompound, melting point 200 C., dec.

The title compound is also prepared from l-benzoyloximino [1 (2acetoxyethyl) 5 nitro-2-imidazoylJ- 2-phenylglyoxal, using the aboveprocedure.

10 EXAMPLE 14 Preparation of1-(l-ethyl-5-nitro-2-imidazo1ecarboximidoyl)-3-thiosemicarbazide Asolution of sodium methoxide (0.060 g., 0.001 mole) and 1 benzoyloximino1 (1 ethyl 5 nitro 2- imidazolyl) 2 phenylglyoxal (0.392 g., 0.001 mole)in 25 ml. of methanol is stirred at room temperature for 2% hours.Thiosemicarbazide (0.091 g., 0.001 mole) and 1 ml. of glacial aceticacid are added and the solution is stirred for 18 hours at roomtemperature. The reaction mixture is diluted With Water andconcentrated. The yellow solid is filtered and washed with water. Thesolid is recrystallized from Water and from ethyl acetateheptane to give0.065 g. of the title compound, melting point 227-229 C., dec.

'EXAMPLE 15 Preparation of 2-amin0-5-( l-methyl-5-nitro-2imidazolyl)-l,3,4-thiadiazo1e from 1-benz0yloximino-1-(l-methyl-S-nitro-2-imidazolyl)-2-phenylglyoxal To a mechanically stirred mixture ofsodium methoxide (0.65 g., 0.012 mole) in 20 ml. of methanol maintainedat 2S30 C. is added 1 benzoyloximino 1 (1-methyl-5-nitro-2-imidazolyl)-2-phenylglyoxal (3.78 g., 0.01 mole). The mixture isstirred at room temperature for 2 /2 hours. Thiosemicarbazide (0.91 g.,0.01 mole) and 1 ml. of glacial acetic acid are added and the mixture isstirred at room temperature for 2 /2 hours. Concentrated hydrochloricacid (2 ml.) is then added and the mixture is heated. After 25 minutes(60 C.) and 35 minutes (65 C.) additional 1 ml. portions of concentratedhydrochloric acid are added and the mixture is heated for 25 minuteslonger. The reaction mixture is made alkaline With concentrated ammoniumhydroxide and the solid is filtered and washed With Water, affording1.28 g. of the title compound, melting point 262 -264 C.

By the above procedure, 2 amino 5 (1 ethyl 5- nitro 2 imidazolyl) 1,3,4thiadiazole is prepared from 1 benzoyloximino 1 (1 ethyl 5 nitro 2-imidazolyl) 2 phenylglyoxal.

In a similar manner, 2 amino 5 [1 (2 hydroxyethyl) 5 nitro 2 imidazolyl]1,3,4 thiadiazole is prepared from both 1 benzoyloximino 1 2acetoxyethyl) 5 nitro 2 imidazolyl] 2 phenylglyoxal and 1 benzoyloximino1 [1-(2-benzoyloxyethyl)-5-nitro- 2 imidazolyl] 2 phenylglyoxal.

According to the above procedure, 2 methylamino 5- l methyl 5 nitro 2imidazolyl) 1,3,4 thiadiazole and 2 dimethylamino 5 (l methyl 5 nitro 2-imidazole) 1,3,4 thiadiazole are prepared by replacing thethiosemicarbazide with 4-methyl-3-thiosemicarbazide and 4,4 dimethyl 3thiosemicarbazide, respectively.

EXAMPLE 16 Preparation of 2 amino 5 (1 methyl 5 nitro 2- imidazolyl)1,3,4 thiadiazole from ethyl l methyl- 5 nitro 2 imidazolecarboximidateTo a stirred solution of ethyl 1 methyl 5 nitro 2-imidazolecarboximidate (0.198 g., 0.001 mole) in 10 ml. of absoluteethanol is added thiosemicarbazide (0.091 g., 0.001 mole) and 20 dropsof cone. hydrochloric acid. The solution is heated at reflux for 30minutes and diluted with water. The aqueous solution is made alkalinewith saturated sodium carbonate solution and the solid is filtered,washed with dried, aifording 0.023 g. of the title compound, meltingpoint 262 -264 C., dec.

In a similar manner, using methyl 1 methyl 5 nitro- 2imidazolecarboximidate, in place of ethyl 1 methyl- 5 nitro 2imidazolecarboximidate, also yields the title compound.

By the above procedure ethyl 1 ethyl 5 nitro 2- imidazolecarboximidateand 1 (2 hydroxyethyl) 5- nitro 2 imidazolecarboximidic aciddelta-lactone yield 11 2 amino (1 ethyl 5 nitro 2 imidazolyl)- 1,3,4thiadiazole and 2 amino 5 [1 (2 hydroxyethyl) 5 nitro 2 imidazolyl]1,3,4 thiadiazole, respectively.

EXAMPLE 17 Preparation of 2-amino-5-( l-methyl-S-nitro-Z- imidazolyl-1,3 ,4-thiadiazole To a stirred mixture of l-(l-methyl- 5-nitro-2-imidazolecarboximidoyl) 3 thiosemicarbazide (0.486 g., 0.002mole) and 5 ml. of methanol is added 1 ml. of saturated ethanolic HCland the mixture is heated at rcflux for 1 hour. The reaction mixture isdiluted With 5 ml. of water and is made alkaline with cone. ammoniumhydroxide. The solid is filtered and washed With water alfording 0.353g. of the title compound, melting point 264"- 266 C., dec.

The above reaction proceeds as well using conc. aqueous HCl in place ofthe saturated ethanolic HCl.

In a similar manner 1 [1 (2 hydroxyethyl) 5- nitro 2imidazolecarboxirnidoyl] 3 thiosemicarbazide gives 2 amino 5 [1 (2hydroxyethyl) 5 nitro 2- imidazolyl] 1,3,4 thiadiazole.

EXAMPLE 18 Preparation of 2-amino-5-(1-ethyl-5-nitro-2-irnidazolyl)-1,3,4-thiadiazole A mixture of 1 (1 ethyl 5 nitro 2imidazolecarboximidoyl) 3 thiosemicarbazide (0.065 g., 0.0025 mole),drops of concentrated hydrochloric acid and 5 ml. of methanol is heatedat reflux for 1 /2 hours. The reaction is diluted with water and madealkaline with concentrated ammonium hydroxide. The solid is filtered,Washed and dried, giving 0.049 g. of the title compound, melting point230231 C.

1. A compound of the formula:

l O R wherein R is a member selected from the group consisting ofloweralkyl, loweralkanoyloxyloweralkyl and aroyloxyloweralkyl wherearoyl is selected from the group consisting of benzoyl, monohalobenzoyl,dihalobenzoyl, loweralkylbenzoyl, diloweralkylbenzoyl, 4-nitrobenzoyl,methoxybenzoyl and naphthoyl; and R is a member selected from the groupconsisting of phenyl, monohalophenyl, dihalophenyl, loweralkylphenyl,diloweralkylphenyl, 4-nitrophenyl, methoxyphenyl and naphthyl.

2. A compound according to claim 1, where R is loweralkyl.

3. A compound according to claim 1, where R isloweralkanoyloxyloweralkyl.

4. A compound according .to claim 1, where R is aroyloxyloweralkyl andaroyl is benzoyl, monohalobenzoyl, di-

12 halobenzoyl, loweralkylbenzoyl, diloweralkylbenzoyl, 4- nitrobenzoyl,methoxybenzoyl or naphthoyl.

5. The compound according to claim 1, l-benzoyloximino-1-(1-methyl-5-nitro-2-imidazolyl) -2-phenylglyoxal.

6. A method for the prepartion of a compound of the where R is a memberselected from the group consisting of loweralkyl,loweralkanoyloxyloweralkyl and aroyloxyloweralkyl, Where aroyl isselected from the group consisting Where R and R are as described above,with 'at least 1 mole equivalent of a nitrosating agent selected fromthe group consisting of nitrosyl chloride, nitrosyl bisulfate, nitrogendioxide, nitrogen trioxide and nitrogen pentoxide, at a temperaturebetween about 0 C. and C. for from about 10 minutes to 24 hours.

7. A method according to claim 6, wherein the reaction is carried out inthe presence of 0.5 to 2 mole equivalents of an alkali. metal salt ofalkanoic acid at a temperature between about 0 and 100 C. and 1 to 10mole equivalents of a nitrosating agent is used.

References Cited UNITED STATES PATENTS 3,472,864 10/ 1969 Henry et al260-309 OTHER REFERENCES Fournari et al., Bull. Soc. Chim., France 1968,pp. 243 8- 46.

Kanno, Chem. Abst., vol. 47, cols. 11154-5 (1953).

Touster, Orangic Reactions, vol. VII, pp. 330-43 and 346-8 (1953).

NATALIE TROUSOF, Primary Examiner U.S. Cl. X.R.

260-240 A, 244 R, 306.8 D, 999

